Project Summary/Abstract This proposal presents a 2-year research fellowship program focused on the study of metabolomic profiling and risk of incident heart failure in the community. The aim of the proposal is to elucidate the role of disturbed metabolism in the development of heart failure in an attempt to uncover novel mechanisms of disease development. The candidate is currently a cardiovascular clinical and research fellow at the Beth Israel Deaconess Medical Center and Harvard Medical School. The fellowship program will entail dedicated training in metabolomic profiling and bioinformatics through a combination of laboratory work and didactics including completion of a Master of Biomedical Informatics Program at Harvard Medical School (MBI). This training will provide the candidate the necessary skill set and expertise to transition to a career development award. The candidate's mentor, Dr. Robert E. Gerszten, is a leading expert in the study of metabolomics and cardiometabolic disease and has led studies of multi-omic profiling in large-scale epidemiological cohorts. The candidate has a diverse and distinguished group of collaborators and is situated in a rich academic institutional environment, providing him with the necessary resources for success during his fellowship. Impaired cardiac and peripheral metabolic processes including significant deficiencies in energy metabolism characterize the heart failure state. However, its unclear to the extent to which these metabolic alterations are present and contribute to the development of heart failure prior to the onset of disease. The emerging field of metabolomics, the study of small molecules or metabolites, allows for deep interrogation of disturbed metabolism and has elucidated novel associations and mechanisms of cardiometabolic disease years before disease onset. In preliminary data on a limited set of metabolites, we identify novel associations of metabolites with incident heart failure in the Jackson Heart Study. We aim to expand our analysis to 300 analytes measured on our platforms, to investigate the associations of metabolic alterations, including impaired fatty acid oxidation with cardiac hypertrophy and incident heart failure (Aims 1 and 2). Further, the applicant will determine whether individuals who develop heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF) carry distinct metabolic signatures prior to onset of disease (Aim 3). The proposed research and aims to determine the association of metabolic alterations with the development of heart failure in an effort to improve understanding of the mechanisms of disease. ! !